The document discusses post-approval changes that can be made to approved NDAs and ANDAs. It describes four reporting categories for post-approval changes based on their potential impact: major changes requiring prior approval, moderate changes reported via a CBE-30 or CBE-0 supplement, minor changes reported annually. Examples are provided for different types of changes that fall under each reporting category. The levels of reporting ensure that manufacturers can make certain changes while providing appropriate notification to the FDA depending on the level of change.

1. US Post Approval ChangesBy,CHANDRAMOHAN

2. • INTRODUCTION
• Types of Post Approval Changes
 Major (PAS)
 Moderate (CBE-30 and CBE-0)
 Minor (AR)
• Examples for Post Approval Changes
• SUPAC

3. • In this presentation, I am going to discuss about the post approval changes and their
reporting categories. After the approval of NDA or ANDA, the applicant may make
post approval changes, provided the changes are reported to the FDA under the
appropriate categories.
• Section 506 A of the Federal Food, Drugs and Cosmetics act and 21 CFR 314.70
provide for 4 reporting categories of the post approval changes which are listed
below-
 21 CFR 314.70 (b) – PAS
 21 CFR 314.70 (c) (3) – CBE-30
 21 CFR 314.70 (c) (6) – CBE-0
 21 CFR 314.70 (c) (7) – Disapproves of CBE-0 and CBE-30
 21 CFR 314.70 (d) (3) – Annual Reports
Introduction

8. Major Changes - PAS
• A major change is a change that has a substantial potential to have an adverse
effect on the identity, strength, quality, purity, or potency of a drug product as
these factors may relate to the safety or effectiveness of the drug product.
• A major change requires the submission of a supplement and approval by FDA
prior to distribution of the drug product made using the change. This type of
supplement is called and should be clearly labelled as Prior approval supplement.
• An applicant may ask FDA to expedite its review of a prior approval supplement
for public health reasons like drug shortage or in case if there is a delay would
impose an extraordinary hardship on the applicant.

9. Moderate Changes
A moderate change is a change that has a moderate potential to have an adverse
effect on the identity, strength, quality, purity, or potency of the drug product as
these factors may relate to the safety or effectiveness of the drug product.
The moderate change is categorized into 2 types based on the type of supplement
being filed -
a) Supplement - Changes Being Effected in 30 Days
This type of change requires submission of supplement to FDA at least 30 days
before the distribution of drug product made using the change.
This type of supplement is called, and should be clearly labelled, a Supplement -
Changes being effected in 30 Days.
The drug product made using moderate changes cannot be distributed if the FDA
informs the applicant to file a prior approval supplement for the changes made or if
FDA informs that the information is missing or if FDA disapproves the changes
being affected in 30 days.

10. Moderate Changes
b) Supplement - Changes Being Effected
This type of supplement contains changes for which distribution can occur
when FDA receives the supplement.
FDA may order the manufacturer to cease distribution of the drug products
made using the disapproved change, If, after review, FDA disapproves a
changes-being effected.

11. Minor changes - AR
• A minor change is a change that has minimal potential to have an adverse effect
on the identity, strength, quality, purity, or potency of the drug product as these
factors may relate to the safety or effectiveness of the drug product.
• Does not require FDA approval prior to distribution of the drug product made
using the change.

12. Reporting changes
• Each change should be described in enough detail in the cover letter or summary
section of the Annual Report to allow FDA to determine whether the appropriate
reporting category has been used.

13. The following information must be contained in a
Prior Approval Supplement
1) A detailed description of the proposed change
2) The drug product(s) involved
3) The manufacturing site(s) or area(s) affected
4) A description of the methods used and studies performed to assess the effects of
the change
5) The data derived from such studies
6) For sterilization process and test methodologies related to sterilization process
validation, relevant validation protocols and a list of relevant standard operating
procedures must be provided in addition to the requirements in 3) and 4)

14. Types of Changes for Prior Approval Supplements
1.) Changes in the qualitative or quantitative formulation of the drug product,
including inactive ingredients or in the specifications
Examples:
• changes in specification of drug concentration, pH, chemical purity (EtOH,
Acetonitrile, K222), NaCl concentration, BET concentration limit, deleting any part
of a specification, etc.
• Establishing a new analytical procedure or a change in an analytical procedure that
does not provide the same or increased assurance of the identity, strength, quality,
purity, or potency of the material being tested as described in the approved
application.

15. Types of Changes for Prior Approval Supplements
2.) Changes that may affect drug product sterility assurance, such as changes in drug
product sterilization method(s) or an addition, deletion, or substitution of steps in an
aseptic processing operation
Examples:
• Addition to an aseptic processing line of new equipment made of different materials
• Deletion of equipment from an aseptic processing line
• Changes in the sterilization method (e.g., filtration, chemical, irradiation)
• Changes in materials or pore size rating of filters used in aseptic processing

16. Types of Changes for Prior Approval Supplements
3.) Changes in the manufacture of the drug substance that may affect the impurity
profile and/or the physical, chemical, or biological properties of the drug substance
Examples:
• Changes in solvents (e.g., acetonitrile to tetrahydrofuran)
• Changes in the precursor (e.g., mannose triflate to mannose tosylate)
• Changes in the resins of the purification columns
• Changes in the hydrolysis method (e.g., acid vs. base, hydrochloric acid to sulfuric
acid or phosphoric acid)
• Changes of the crown ether used to complex the cation

17. Types of Changes for Prior Approval Supplements
4.) Labelling changes
Examples:
• Changes based on post-marketing study results, including, but not limited to,
labelling changes associated with new indications and usage.
• Revision (expansion or contraction) of population based on data.
• Claims of superiority to another drug product.

18. Types of Changes for Prior Approval Supplements
5.) Changes in container closure system
Examples:
• Changes in a drug product container closure system that controls the drug product
delivered to a patient.
• Changes in the type (e.g., glass to high density polyethylene (HDPE), vial to
syringe) or composition (e.g., one HDPE resin to another HDPE resin) of a
packaging component that may affect the impurity profile of the drug product

19. Types of Changes for Prior Approval Supplements
6.) Site change to different manufacturing site which doesn’t have satisfactory GMP
status within 2 yrs.
7.) Replacement of equipment with another equipment which has different design &
different operating principle.
8.) Fundamental change in the process (eg. Wet granulation to dry granulation or
vise versa)
9.) Change in the route of the synthesis for a drug substance.
10.) Changing an analytical procedure for the finished product if the change is not
compendial.

20. The following information must be contained in a
CBE-30 Supplement
1) Full explanation of the basis for the change.
2) The date on which the change is to be made.
• The applicant must wait 30 days after submission of the CBE-30 Supplement
before distributing the drug product made using the change
• If the FDA informs the applicant within 30 days of the submission that any
information is missing, the applicant must not distribute the drug product made
using the change until the supplement has been amended to provide the missing
information
• The FDA may inform the applicant that the change needs to be resubmitted as a
Prior Approval Supplement

21. Types of Changes for CBE-30 Supplements
1.) Any change in process and/or process parameters.
Examples:
• Changes in concentration of reactants, reaction times, reaction temperatures and
pressures.
• Changes in the order of addition of reactants.
• Changes in reaction pH.
• Changes in final distillation temperatures (e.g., water content of anhydrous steps).

22. Types of Changes for CBE-30 Supplements
2.) A change in the container closure system that does not affect the quality of the
drug product.
Examples:
• Changes in the size or shape of a container for a sterile drug substance (The new
container having the same quality glass, septum and crimp.)

23. Types of Changes for CBE-30 Supplements
3.) Relaxation of an acceptance criterion or deletion of a test to comply with an
official compendium that is consistent with FDA regulatory requirements.
Examples:
• Relaxing an acceptance criterion or deleting a test for raw materials used in drug
substance manufacturing (e.g., increasing the melting point range for mannose
triflate, deleting the appearance acceptance criteria for mannose triflate or K222)
• Making a change to an analytical procedure used for testing raw materials or drug
substance intermediates that does not provide the same or increased quality
assurance as the analytical procedure described in the approved application.

24. Types of Changes for CBE-30 Supplements
4.) Addition of new PET manufacturing sites.
• Additional facilities are required to be shown to operate identical to currently
approved sites.
• A product comparability protocol is required by the FDA to be submitted with the
CBE-30 supplement for the addition of new sites.

25. Types of Changes for CBE-30 Supplements
5.) Labeling changes.
Examples:
• Addition of an adverse event due to information reported to the applicant or
Agency.
• Addition of a precaution arising out of a post-marketing study.

26. Types of Changes for CBE-30 Supplements
6.) Site change to different manufacturing site for DP, DS which has satisfactory
GMP status within 2 yrs.
7.) Replacement of equipment with another equipment which has different design &
same operating principle.
8.) Change in analytical procedure with an equivalent procedure (eg. Method change
from HPLC to UV)

27. Submission of CBE-0 Supplements
For certain types of changes, the holder of an approved application may commence
distribution of the drug product upon receipt by the agency of a supplement for the
change (i.e., there is no waiting period)
• If, after reviewing a CBE-0 supplement, FDA disapproves the change, FDA may
order the manufacturer to cease distribution of the drug product made using the
change.
• If FDA informs the applicant that any information is missing, the applicant must
cease distributing the drug product made using the change until the supplement has
been amended to provide the missing information.

28. Types of Changes for CBE-0 Supplements
1.) Addition to a specification or changes in the methods or controls to provide
increased assurance that the drug substance or drug product will have the
characteristics of identity, strength, quality, purity, or potency that it purports or is
represented to possess.
Examples:
• Adding a new test and associated analytical procedure and acceptance criterion.
• Improving an HPLC or GC method to increase the peak resolution.
• Increase the frequency of CIDG impurity testing.

29. Types of Changes for CBE-0 Supplements
2.) Changes in the labeling to reflect newly acquired information to accomplish any
of the following:
• To add or strengthen a contraindication, warning, precaution, or adverse reaction.
• To add or strengthen an instruction about dosage and administration that is
intended to increase the safe use of the drug product.
• To delete false, misleading, or unsupported indications for use or claims for
effectiveness.

30. Types of Changes for CBE-0 Supplements
3.) Change in manufacturing site for the final intermediate of drug substance.
4.) Change in test method or controls for assuring better product quality.
5.) Change or addition/deletion of a desiccant.

31. Annual Report
Changes in the drug substance, drug product, production process, quality controls,
equipment, or facilities that have a minimal potential to have an adverse effect on
the identity, strength, quality, purity, or potency of the drug product do not need to
be reported to the FDA immediately, but can be reported in the submission of the
next scheduled Annual Report.

32. Types of changes reported in Annual Reports
1.) Any change made to comply with a change to an official compendium that is
consistent with FDA regulatory requirements.
Example:
• Change of USP CIDG specification from 1.0 mg/dose to 0.125 mg/mL

33. Types of changes reported in Annual Reports
2.) Replacement of equipment with that of the same design and operating principles
Example:
• Replace Agilent GC with a Bruker GC using the same column and detector

34. Types of changes reported in Annual Reports
3.) The addition or revision of an alternative analytical procedure that provides the
same or increased assurance of the identity, strength, quality, purity, or potency of
the material being tested as the analytical procedure described in the approved
application.
Example:
• Add PTS as an alternative to the gel-clot test for BET

35. Types of changes reported in Annual Reports
4.) Tightening of acceptance criteria.
Examples:
• Reduce acceptance criteria concentrations for acetonitrile, K222 and BET
• Increase radiochemical purity criteria.

36. Types of changes reported in Annual Reports
5.) A change in the labeling concerning the description of the drug product or in the
information about how the drug product is supplied, that does not involve a change
in the dosage strength.
Examples:
• Changes in the layout of the package or container label that are consistent with
FDA regulations without a change in the content of the labelling.
• Editorial changes, such as adding a distributor's name.
• Labelling changes made to comply with an official compendium.

37. Types of changes reported in Annual Reports
6.) Minor structural modifications with in an approved manufacturing facility.
7.) Batch size up to 10 folds
8.) Change in equipment of same design and operating principle.
9.) Non automated equipment to automated
10.) Site change for labeling operation or secondary packaging.
11.) Addition or deletion of embossing/debossing in tablet dosage form.
12.) Extension of expiration dating based on complete shelf life data.

38. Types of changes reported in Annual Reports
Components And Composition:
• Elimination or reduction of an overage from the drug product manufacturing batch
formula.
• Change in coating formulation, if the coating material have been approved for
another similar product and the change does not alter release of the drug,
specification or stability.
• The supplier of an inactive ingredient was specified in an approved application,
change to a new supplier of that inactive ingredient (e.g., change from one drug
master file (DMF) holder to other DMF holder or change to a new qualified
supplier). This is applicable only if the inactive ingredient’s specification remains
unchanged.

39. Manufacturing Sites
• Minor structural modifications made in an approved manufacturing facility.
Manufacturing Process, Batch Size, and Equipment
• Addition of a sieving step(s)
• Changes in mixing times (for blending powders, granules)
• Changes in drying times.
• Manufacturing batch size within 10 folds.
• Equipment replacement with that of the same design and operating principle.
• Decrease in the number of open handling steps or manual operation procedures.
Types of changes reported in Annual Reports

40. Specifications
• Addition of a new test to the specification for an excipient.
• Change to the specification for a drug substance, drug product, or pharmacopeial excipient that is
made to comply with the official compendia.(Specification changes not suitable for documentation
in an annual report include changes to an assay, tests for impurities, degradation products, product-
related substances, or biological activities that are approved in NDAs and ANDAs. Such changes
should be submitted in a supplement.)
• Change in the approved analytical procedure if the revised method maintains the original test
methodology and provides equivalent or increased assurance that the drug substance or drug
product.
• Addition of an in-process test.
• Revision of tablet hardness if there is no change in the approved dissolution
• Addition of a test for packaging material
• Tightening of an approved acceptance criterion for a drug substance, a drug product, drug product
formulation components, and in-process material.
Types of changes reported in Annual Reports

41. Container/Closure System
• A change in the container/closure system for the storage
• Transfer to a contract manufacturing organization (CMO) for the washing, drying,
or/and siliconization of a drug product stopper or any part of a container closure
system
• For solid oral dosage forms, when the change is to use another suitable primary
packaging component used in any other CDER-approved drug product:
Change in type of desiccant to another desiccant that was previously used in
another approved product and is suitable for its intended use.
Elimination of a bottle filler, such as a fibrous material (e.g., suitable type of
cotton, rayon, polyester, etc.) that is used to fill empty or void space in the
finished product container.
• Change to delete the company trademark or other markings on the crimp cap
Types of changes reported in Annual Reports

42. Labeling Changes
• Revision in drug product labeling to reflect the qualitative change in inactive
ingredient(s) of coating formulation,
• A change in the drug product labeling to revise information related to CMC
changes.
Miscellaneous Changes
• Extension of the drug substance retest dating period or drug product expiration
dating period based on real-time stability data
• For immediate release solid oral dosage forms, if a dissolution test is performed,
elimination of a test for identity or hardness from an approved stability protocol.
Types of changes reported in Annual Reports

43. SUPAC-Scale-Up and Post Approval Changes

44. Level of changes
Likelihood of impact on formulation quality and performance
• Level 1: Unlikely to have detectable
• Level 2: Could have significant impact
• Level 3: Likely to have significant impact

45. SUPAC
These guidelines provide recommdation for post approval changes in
1. The component or composition
2. The site of manufacture
3. The scale up of manufacture, and
4. The manufacturing (process and equipment)